Extended release formulation

ABSTRACT

This invention relates to a 24 hour extended release dosage formulation and unit dosage form thereof of venlafaxine hydrochloride, an antidepressant, which provides better control of blood plasma levels than conventional tablet formulations which must be administered two or more times a day and fiber provides a lower incidence of nausea and vomiting than the conventional tablets. More particularly, the invention comprises an extended release formulation of venlafaxine hydrochloride comprising a therapeutically effective amount of venlafaxine hydrochloride in spheroids comprised of venlafaxine hydrochloride, microcrystalline cellulose and, optionally, hydroxypropylmethylcellulose coated with a mixture of ethyl cellulose and hydroxypropylmethylcellulose.

[0001] This application continuation-in-part of application Ser. No.08/964,328, filed Nov. 5, 1997, which is a continuation-in-part ofcopending application Ser. No. 08/821,137, filed Mar. 20, 1997, which,in turn, claims priority from Provisional Application No. 60/014,006filed Mar. 25, 1996.

BACKGROUND OF THE INVENTION

[0002] Extended release drug formulations are conventionally produced ascompressed tablets by hydrogel tablet technology. To produce thesesustained release tablet drug dosage forms, the active ingredient isconventionally compounded with cellulose ethers such as methylcellulose, ethyl cellulose or hydroxypropylmethylcellulose with orwithout other excipients and the resulting mixture is pressed intotablets. When the tablets are orally administered, the cellulose ethersin the tablets swell upon hydration from moisture in the digestivesystem, thereby limiting exposure of the active ingredient to moisture.As the cellulose ethers are gradually leached away by moisture, watermore deeply penetrates the gel matrix and the active ingredient slowlydissolves and diffuses through the gel, making it available forabsorption by the body. An example of such a sustained release dosage,form of the analgesic/anti-inflammatory drug etodolac (Lodin) appears inU.S. Pat. No. 4,966,768. U.S. Pat. No. 4,389,393 discloses sustainedrelease therapeutic compressed solid unit dose forms of an activeingredient plus a carrier base comprised of a high molecular weighthydroxypropylmethylcellulose, methyl cellulose, sodiumcarboxymethylcellulose and or other cellulose ether.

[0003] Where the production of tablets is not feasible, it isconventional in the drug industry to prepare encapsulated drugformulations which provide extended or sustained release properties. Inthis situation, the extended release capsule dosage forms may beformulated by mixing the drug with one or more binding agents to form auniform mixture which is then moistened with water or a solvent such asethanol to form an extrudable plastic mass from which small diameter,typically 1 mm, cylinders of drug/matrix are extruded, broken intoappropriate lengths and transformed into spheroids using standardspheronization equipment. The spheroids, after drying, may then bethin-coated to retard dissolution. The fin-coated spheroids may then beplaced in pharmaceutically acceptable capsules, such as starch orgelatin capsules, in the quantity needed to obtain the desiredtherapeutic effect. Spheroids releasing the drug at different rates maybe combined in a capsule to obtain desired release rates and bloodlevels. U.S. Pat. No. 4,138,475 discloses a sustained releasepharmaceutical composition consisting of a hard gelatin capsule filledwith film-coated spheroids comprised of propanolol in admixture withmicrocrystalline cellulose wherein the film coating is composed of ethylcellulose, optionally, with hydroxypropylmethylcellulose and/or aplasticizer.

[0004] Venlafaxine,1-[2-(dimethylamino)-1-(4methoxyphenyl)ethyl]cyclohexanol, is animportant drug in the neuropharmacological arsenal used for treatment ofdepression. Venlafaxine and the acid addition salts thereof aredisclosed in U.S. Pat. No. 4,535,186. Venlafaxine hydrochloride ispresently administered to adults in compressed tablet form in dosesranging from 75 to 350 mg/day, in divided doses two or three times aday. La therapeutic dosing with venlafaxine hydrochloride tablets, rapiddissolution results in a rapid increase in blood plasma levels of theactive compound shortly after administration followed by a decrease inblood plasma levels over several hours as the active compound iseliminated or metabolized, until sub-therapeutic plasma levels areapproached after about twelve hours following administration, thusrequiting additional dosing with the drug. With the plural daily dosingregimen the most common side effect is nausea, experienced by aboutforty five percent of patients under treatment with venlafaxinehydrochloride. Vomiting also occurs in about seventeen percent of thepatients.

BRIEF DESCRIPTION OF THE INVENTION

[0005] In accordance with this invention, there is provided an extendedrelease (ER), encapsulated formulation containing venlafaxinehydrochloride as the active drug component, which provides in a singledose, a therapeutic blood serum level over a twenty four hour period.

[0006] Through administration of the venlafaxine formulation of thisinvention, there is provided a method for obtaining a flattened drugplasma concentration to time profile, thereby affording a tighter plasmatherapeutic range control than can be obtained with multiple dailydosing. In other words, this invention provides a method for eliminatingthe sharp peaks and troughs hills and valleys) in blood plasma druglevels induced by multiple daily dosing with conventional immediaterelease venlafaxine hydrochloride tablets. In essence, the plasma levelsof venlafaxine hydrochloride rise, after administration of the extendedrelease formulations of this invention, for between about five to abouteight hours (optimally about six hours) and then begin to fall through aprotracted, substantially linear decrease from the peak plasma level forthe remainder of the twenty four hour period, maintaining at least athreshold therapeutic level of the drug during the entire twenty-fourperiod. In contrast, the conventional immediate release venlafaxinehydrochloride tablets give peak blood plasma levels in 2 to 4 hours.Hence, in accordance with the use aspect of this invention, there isprovided a method for moderating the -plural blood plasma peaks andvalleys attending the pharmacokinetic utilization of multiple dailytablet dosing with venlafaxine hydrochloride which comprisesadministering to a patient in need of treatment with venlafaxinehydrochloride, a one-a-day, extended release formulation of venlafaxinehydrochloride.

[0007] The use of the one-a-day venlafaxine hydrochloride formulationsof this invention reduces by adaptation, the level of nausea andincidence of emesis that attend the administration of multiple dailydosing. In clinical trials of venlafaxine hydrochloride ER, theprobability of developing nausea in the course of the trials was greatlyreduced after the first week. Venlafaxine ER showed a statisticallysignificant improvement over conventional venlafaxine hydrochloridetablets in two eight-week and one 12 week clinical studies. Thus, inaccordance with this use aspect of the invention there is provided amethod for reducing the level of nausea and incidence of emesisattending the administration of venlafaxine hydrochloride whichcomprises dosing a patient in need of treatment with venlafaxinehydrochloride with an extended release formulation of venlafaxinehydrochloride once a day in a therapeutically effective amount.

[0008] The formulations of this invention comprise an extended releaseformulation of venlafaxine hydrochloride comprising a therapeuticallyeffective amount of venlafaxine hydrochloride in spheroids comprised ofvenlafaxine hydrochloride, microcrystalline cellulose and, optionally,hydroxypropylmethylcellulose coated with a mixture of ethyl celluloseand hydroxypropylmethylcellulose. Unless otherwise noted, the percentagecompositions mentioned herein refer to percentages of the total weightof the final composition or formulation.

[0009] More particularly, the extended release formulations of thisinvention are those above wherein the spheroids are comprised of fromabout 6% to about 40% venlafaxine hydrochloride by weight, about 50% toabout 95% microcrystalline cellulose, NF, by weight, and, optionally,from about 0.25% to about 1% by weight of hydroxypropylmethylcellulose,USP, and coated with from about 2% to about 12% of total weight of filmcoating comprised of from about 80% to about 90% by weight of filmcoating of ethyl cellulose, NF, and from about 10% to about 20% byweight of film coating of hydroxypropylmethylcellulose, USP.

[0010] A preferred embodiment of this invention are formulations whereinthe spheroids are comprised of about 30% to about 40% venlafaxinehydrochloride by weight, about 50% to about 70% microcrystallinecellulose, NT, by weight, and, optionally, from about 0.25% to about 1%by weight of hydroxypropylmethylcellulose, USP, and coated with fromabout 2% to about 12% of total weight of film coating comprised of fromabout 80% to about 90% by weight of film coating of ethyl cellulose, NF,and from about 10% to about 20% by weight of film coating ofhydroxypropylmethylcellulose, USP.

[0011] Another preferred lower dose formulation of this invention arethose wherein the spheroids are comprised less than 30% venlafaxinehydrochloride. These formulations comprise spheroids of from about 6% toabout 30% venlafaxine hydrochloride by weight, about 70% to about 94%microcrystalline cellulose, NF, by weight, and, optionally, from about0.25% to about 1% by weight of hydroxypropylmethylcellulose, USP, andcoated with from about 2% to about 12% of total weight of film coatingcomprised of from about 80% to about 90% by weight of film coating ofethyl cellulose, NF, and from about 10% to about 20% by weight of filmcoating of hydroxypropylmethylcellulose, USP.

[0012] Within this subgroup of lower dose formulations are formulationsin which the spheroids are comprised of from about 6% to about 25%venlafaxine hydrochloride and from about 94% to about 75%microcrystalline cellulose, with an optional amount of from 0.25% toabout 1% by weight of hydroxypropylmethylcellulose. Another preferredsubgroup of spheroids in these formulations comprises from about 6% toabout 25% venlafaxine hydrochloride and from about 94% to about 75%microcrystalline cellulose, with an optional amount of from 0.25% toabout 1% by weight of hydroxypropylmethylcellulose. A ether preferredsubgroup of spheroids in these formulations comprises from about 6% toabout 20% venlafaxine hydrochloride and from about 94% to about 80%microcrystalline cellulose, with an optional amount of from 0.25% toabout 1% by weight of hydroxypropylmethylcellulose. Within each of thesesubgroups is understood to be formulations in which the spheroids arecomprised of venlafaxine HCT and microcrystalline cellulose in theamounts indicated, with no hydroxypropylmethylcellulose present Each ofthese formulations is also preferably contained in a gelatin capsule,preferably a bard gelatin capsule.

DETAILED DESCRIPTION OF THE INVENTION

[0013] 1-[2-(dimethylamino)-1-(4methoxyphenyl)ethyl]cyclohexanolhydrochloride is polymorphic. Of the forms isolated and characterized todate, Form I is considered to be the kinetic product of crystallizationwhich can be converted to Form II upon heating in the crystallizationsolvent. Forms I and II cannot be distinguished by their melting pointsbut do exhibit some differences in their infrared spectra and X-raydiffraction patterns. Any of the polymorphic forms such as Form I orForm II may be used in the formulations of the present invention.

[0014] The extended release formulations of this invention are comprisedof 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanolhydrochloride in admixture with microcrystalline cellulose andhydroxypropylmethylcellulose. Formed as beads or spheroids, the drugcontaining formulation is coated with a mixture of ethyl cellulose andhydroxypropylmethyl cellulose to provide, the desired level of coating,generally from about two to about twelve percent on a weight/weightbasis of final product or more preferably from about five to about tenpercent (w/w), with best results obtained at from about 6 to about 8percent (w/w). More specifically, the extended release spheroidformulations of this invention comprise from about 30 to 40 percentvenlafaxine hydrochloride, from about 50 to about 70 percentmicrocrystalline cellulose, NF, from about 0.25 to about 1 percenthydroxypropylmethylcellulose, USP, and from about 5 to about 10 percentfilm coating, all on a weight/weight basis. And preferably, the spheroidformulations contain about 35 percent venlafaxine hydrochloride, about55 to 60 percent microcrystalline cellulose NF (Avicel® PH101), aboutone half percent hydroxypropylmethylcellulose 2208 USP (K3, Dow, whichhas a viscosity of 3 cps for 2% aqueous solutions, a methoxy content of19-24% and a hydroxypropoxy content of 4-13%), and from about 6 to 8percent film coating.

[0015] The film coating is comprised of 80 to 90 percent of ethylcellulose, NF and 10 percent hydroxypropylmethylcellulose (2910), USP ona weight/weight basis. Preferably the ethyl cellulose has a ethoxycontent of 44.0-51% and a viscosity of 50 cps for a 5% aqueous solutionand the hydroxypropylmethylcellulose is USP 2910 having a viscosity of 6cps at 2% aqueous solution with a methoxy content of 28-30% and ahydroxypropoxy content of 7-12%. The ethyl cellulose used herein isAqualon HG 2834.

[0016] Other equivalents of the hydroxypropylmethylcelluloses 2208 and2910 USP and ethyl cellulose, NF, having the same chemical and physicalcharacteristics as the proprietary products named above may besubstituted in the formulation without changing the inventive concept.Important characteristics of suitable hydroxypropylmethylcellulosesinclude a low viscosity, preferably less than 10 cps and more preferably2-5 cps, and a gel temperature above that of the temperature of theextrudate during extrusion. As explained below, these and othercharacteristics which enable the extrudate to remain moist and soft(pliable) are preferred for the hydroxypropylmethylcellulose. In theexamples below, the extrudate temperature was generally 50-55° C.

[0017] It was completely unexpected that an extended release formulationcontaining venlafaxine hydrochloride could be obtained because thehydrochloride of venlafaxine proved to be extremely water soluble.Numerous attempts to produce extended release tablets by hydrogeltechnology proved to be fruitless because the compressed tablets wereeither physically unstable (poor compressibility or capping problems) ordissolved too rapidly in dissolution studies. Typically, the tabletsprepared as hydrogel sustained release formulations gave 40-50%dissolution at 2 brs, 60-70% dissolution at 4 hrs and 85-100%dissolution at 8 hrs.

[0018] Numerous spheroid formulations were prepared using differentgrades of microcrystalline cellulose and hydroxypropylmethylcellulose,different ratios of venlafaxine hydrochloride and filler, differentbinders such as polyinylpyrrolidone, methylcellulose, water, andpolyethylene glycol of different molecular weight ranges in order tofind a formulation which would provide a suitable granulation mix whichcould be extruded properly. In the extrusion process, heat buildupoccurred which dried out the extrudate so much that it was difficult toconvert the extruded cylinders into spheroids. Addition ofhydroxypropylmethylcellulose 2208 -to the venlafaxinehydrochloride-microcrystalline cellulose mix made production ofspheroids practical.

[0019] The encapsulated formulations of this invention may be producedin a uniform dosage for a specified dissolution profile upon oraladministration by techniques understood in the art. For instance, thespheroid components may be blended for uniformity with a desiredconcentration of active ingredient, then spheronized and dried. Theresulting spheroids can then be sifted through a mesh of appropriatepore size to obtain a spheroid batch of uniform and prescribed size.

[0020] The resulting spheroids can be coated and resifted to remove anyagglomerates produced in the coating steps. During the coating processsamples of the coated spheroids may be tested for their distributionprofile. If the dissolution occurs too rapidly, additional coating maybe applied until the spheroids present a desired dissolution rate.

[0021] The following examples are presented to illustrate applicant'ssolution to the problem of preparation of the extended release drugcontaining formulations of this invention.

EXAMPLE NO. 1

[0022] Venlafaxine Hydrochloride Extended Release Capsules

[0023] A mixture of 44.8 parts ( 88.4% free base) of venlafaxinehydrochloride, 74.6 parts of the microcrystalline cellulose, NF, and0.60 parts of hydroxypropylmethyl cellulose 2208, USP, are blended withthe addition of 41.0 parts water. The plastic mass of material isextruded, spheronized and dried to provide uncoated drug containingspheroids.

[0024] Stir 38.25 parts of ethyl cellulose, NF, HG2834 and 6.75 parts ofhydroxypropylmethylcellulose 2910, USP in a 1:1 v/v mixture of methylenechloride and anhydrous methanol until solution of the film coatingmaterial is complete.

[0025] To a fluidized bed of the uncoated spheroids is applied 0.667parts of coating solution per part of uncoated spheroids to obtainextended release, film coated spheroids having a coating level of 3%.

[0026] The spheroids are sieved to retain the coated spheroids of aparticle size between 0.85 mm to 1.76 mm diameter. These selected filmcoated spheroids are filled into pharmaceutically acceptable capsulesconventionally, such as starch or gelatin capsules.

EXAMPLE NO. 2

[0027] Same as for Example 1 except that 1.11 parts of the film coatingsolution per part of uncoated spheroids is applied to obtain a coatinglevel of 5%.

EXAMPLE NO. 3

[0028] Same as for Example 1 except that 1.33 parts of the film coatingsolution is applied to 1 part of uncoated spheroids to obtain a coatinglevel of 6%.

EXAMPLE NO. 4

[0029] Same as for Example 1 except that 1.55 parts of the film coatingsolution is applied to 1 part of uncoated spheroids to obtain a coatinglevel of 7%.

[0030] In the foregoing failed experiments and in Examples 1-4, theextrusion was carried out on an Alexanderwerk extruder. Subsequentexperiments carried out on Hutt and Nica extruders surprisinglydemonstrated that acceptable, and even improved, spheroids could be madewithout the use of an hydroxypropylmethylcellulose.

[0031] In such fierier experiments the applicability of the inventionwas extended to formulations wherein the weight percentage ofvenlafaxine hydrochloride is 6% to 40%, preferably 8% to 35%. Thus, theextended release spheroid formulations of this invention comprise fromabout 6 to about 40 percent venlafaxine hydrochloride, from about 50 toabout 94 percent microcrystalline cellulose, NF, optionally, from about0.25 to about 1 percent hydroxypropylmethylcellulose, and from about 2to about 12 percent, preferably about 3 to 9 percent, film coating.

[0032] Spheroids of the invention were produced having 8.25% (w/w)venlafaxine hydrochloride and the remainder (91.75%, w/w) beingmicrocrystalline cellulose, with a coating of from 3 to 5% (w/w),preferably 4%, of the total weight. The spheroids with 8.25% venlafaxinehydrochloride and 4% coating were filled into No. 2 white opaque shellswith a target fill weight of 236 mg.

[0033] Further spheroids of the invention were produced having 16.5%(w/w) venlafaxine hydrochloride and the remainder (83.5%,w/w) beingmicrocrystalline cellulose, with a coating of from 4 to 6% (w/w),preferably 5%, of the total weight. The spheroids 16.5% venlafaxinehydrochloride and 5% coating were filled into No. 2 white opaque shellswith a target fill weight of 122 mg.

[0034] The test for acceptability of the coating level is determined byanalysis of the dissolution rate of the finished coated spheroids priorthe encapsulation. The dissolution procedure followed uses USP Apparatus1 (basket) at 100 rpm in purified water at 37° C.

[0035] Conformance with the dissolution rate given in Table 1 providesthe twenty-four hour therapeutic blood levels for the drug component ofthe extended release capsules of this invention in capsule form. Where agiven batch of coated spheroids releases drug too slowly to comply withthe desired dissolution rate study, a portion of uncoated spheroids orspheroids with a lower coating level may be added to the batch toprovide, after thorough mixing, a loading dose for rapid increase ofblood drug levels. A batch of coated spheroids that releases the drugtoo rapidly can receive additional film-coating to give the desireddissolution profile. TABLE 1 Acceptable Coated Spheroid DissolutionRates Time (hours) Average % Venlafaxine HCl released 2 <30 4 30-55 855-80 12  65-90 24  >30

[0036] Batches of the coated venlafaxine hydrochloride containingspheroids which have a dissolution rate corresponding to that of Table 1are filled into pharmaceutically acceptable capsules in an amount neededto provide the unit dosage level desired. The standard unit dosageimmediate release (IR) tablet used presently provides amounts ofvenlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg and100 mg venlafaxine. The capsules of this invention are filled to providean amount of venlafaxine hydrochloride equivalent to that presently usedin tablet form and also up to about 150 mg venlafaxine hydrochloride.

[0037] Dissolution of the venlafaxine hydrochloride ER capsules isdetermined as directed in the U.S. Pharmacopoeia (JSP) using apparatus 1at 100 rpm on 0.9 L of water. A filtered sample of the dissolutionmedium is taken at the times specified. The absorbance of the clearsolution is determined from 240 to 450 nanometers (nm) against thedissolution medium. A baseline is drawn from 450 am through 400 nm andextended to 240 nm. The absorbance at the wavelength of maximumabsorbance (about 274 mm) is determined with respect to this baseline.Six hard gelatin capsules are filled with the theoretical amount ofvenlafaxine hydrochloride spheroids and measured for dissolution.Standard samples consist of venlafaxine hydrochloride standard solutionsplus a gelatin capsule correction solution.

[0038] The percentage of venlafaxine released is determined from theequation${\% \quad {Venlafaxine}\quad {hydrochloride}\quad {released}} = \frac{({As})({Wr})(S)({V1})(0.888)(100)}{({Ar})({V2})(C)}$

[0039] where As is absorbance of sample preparation, Wr is weight ofreference standard, mg; S is strength of the reference standard,decimal; V1 is the volume of dissolution medium used to dissolve thedosage form, mL; 0.884 is the percent free base, Ar is the absorbance ofthe standard preparation, V2 is the volume of reference standardsolution, mL; and C is the capsule claim in mg.

[0040] Table 2 shows the plasma level of venlafaxine versus time for one75 mg conventional Immediate Release (IR) tablet administered every 12hours, two 75 mg extended release (ER) capsules administeredsimultaneously every 24 hours, and one 150 mg extended release (ER)capsule administered once every 24 hours in human male subjects. Thesubjects were already receiving venlafaxine hydrochloride according tothe dosage protocol, thus the plasma blood level at zero time whendosages were administered is not zero. TABLE 2 Plasma venlafaxine level(ng/mL) versus time, conventional tablet (not extended release) versusER causule 75 mg 2 × 75 mg 1 × 150 mg (IR) tablet (ER) capsules (ER)capsules Time (hours) (q 12 h) (q 24 hr) (q 24 h) 0 62.3 55.0 55.8 0.576.3 1 135.6 53.3 53.2 2 212.1 69.8 70.9 4 162.0 138.6 133.3 6 114.6149.0 143.5 8 86.7 129.3 129.5 10 118.4 114.4 12 51.9 105.1 105.8 12.574.7 13 127.5 14 161.3 90.5 91.3 16 134.6 78.2 78.5 18 106.2 20 83.662.7 63.3 24 57.6 56.0 57.3

[0041] Table 2 shows that the plasma levels of two 75 mg/capsulevenlafaxine hydrochloride ER capsules and one 150 mg/capsule venlafaxinehydrochloride ER capsule provide very similar blood levels. The dataalso show that the plasma level after 24 hours for either extendedrelease regimen is very similar to that provided by two immediaterelease 75 mg tablets of venlafaxine hydrochloride administered at 12hour intervals.

[0042] Further, the plasma levels of venlafaxine obtained with theextended release formulation do not increase to the peak levels obtainedwith the conventional immediate release tablets given 12 hours apart.The peak level of venlafaxine from (ER), somewhat below 150 ng/ml, isreached in about six hours, plus or minus two hours, based upon thisspecific dose when administered to patients presently under treatmentwith venlafaxine hydrochloride (IR). The peak plasma level ofvenlafaxine, somewhat over 200 ng/ml, following administration of (IR)is reached in two hours and falls rapidly thereafter.

[0043] Table 3 shows venlafaxine blood plasma levels in male humansubjects having a zero initial blood plasma level. Again, a peak bloodplasma concentration of venlafaxine is seen at about 6 hours afterdosing with venlafaxine hydrochloride extended release capsules in thequantities indicated The subjects receiving the single 50 mg immediaterelease tablet showed a peak plasma level occurring at about 4 hours.For comparative purposes, the plasma levels of venlafaxine for subjectsreceiving the conventional formulated tablet can be multiplied by afactor of three to approximate the plasma levels expected for a singledose of 150 mg. conventional formulation. TABLE 3 Plasma Blood Levels inHuman Males Having No Prior Venlafaxine Blood Level Time 1 × 50 mg 2 ×75 mg 1 × 150 mg (Hours) IR tablet ER capsules ER capsule 0 0 0 0 127.87 1.3 0 1.5 44.12 6.0 2.2 2 54.83 20.6 12.8 4 66.38 77.0 81.0 649.36 96.5 94.4 8 30.06 93.3 86.9 10 21.84 73.2 72.8 12 15.91 61.3 61.414 13.73 52.9 51.9 16 10.67 47.5 41.1 20 5.52 35.2 34.0 24 3.56 29.328.5 28 2.53 23.4 22.9 36 1.44 11.9 13.5 48 0.66 5.8 5.2

[0044] The blood plasma levels of venlafaxine were measured according tothe following procedure. Blood samples from the subjects were collectedin heparinized evacuated blood tubes and the tubes were inverted gentlyseveral times. As quickly as possible, the tubes were centrifuged at2500 rpm for 15 minutes. The plasma was pipetted into plastic tubes andstored at −20° C. until analysis could be completed.

[0045] To 1 mL of each plasma sample in a plastic tube was added 150 μLof a stock internal standard solution (150 μg/ml). Saturated sodiumborate (0.2 mL) solution was added to each tube and vortexed. Five mL ofethyl ether was added to each tube which were then capped and shaken for10 minutes at high speed. The tubes were centrifuged at 3000 rpm for 5minutes. The aqueous layer was frozen in dry ice and the organic layertransferred to a clean screw cap tube. A 0.3 ml portion of 0.01 N HClsolution was added to each tube and shaken for 10 minutes at high speed.The aqueous layer was frozen and the organic layer removed anddiscarded. A 50 μL portion of the mobile phase (23:77 acetonitrile:0.1Mmonobasic ammonium phosphate buffer, pH 4.4) was added to each tube,vortexed, and 50 μL samples were injected on a Superco SupercoilLC-8-DB, 5 cm×4.6 mm, 5 μ column in a high pressure liquidchromatography apparatus equipped with a Waters Lambda Max 481 detectoror equivalent at 229 nm. Solutions of venlafaxine hydrochloride atvarious concentrations were used as standards.

EXAMPLE NO. 5

[0046] Manufactured by the techniques described herein, anotherpreferred formulation of this invention comprises spheroids of fromabout 30% to about 35% venlafaxine hydrochloride and from about 0.3% toabout 0.6% hydroxypropylmethylcellulose. These spheroids are then coatedwith a film coating, as described above, to a coating level of fromabout 5% to about 9%, preferably from about 6% to about 8%. A specificformulation of this type comprises spheroids of about 33% venlafaxinehydrochloride and about 0.5% hydroxypropylmethylcellulose, with a filmcoating of about 7%.

[0047] Lower dosage compositions or formulations of this invention mayalso be produced by the techniques described herein. These lower dosageforms may be administered alone for initial titration or initiation oftreatment, prior to a dosage increase. They may also be used for anoverall low-dose administration regimen or in combination with higherdosage compositions, such as capsule formulations, to optimizeindividual dosage regimens.

[0048] These lower dose compositions may be used to create encapsulatedformulations, such as those containing doses of venlafaxinehydrochloride from about 5 mg to about 50 mg per capsule. Particularfinal encapsulated dosage forms may include, but are not limited to,individual doses of 7.5 mg, 12.5 mg, 18.75 mg, or 28.125 mg ofvenlafaxine HCl per capsule.

[0049] The spheroids useful in these lower dose formulations maycomprise from about 5% to about 29.99% venlafaxine HCl, preferably fromabout 5% to about 25%, from about 75% to about 95% microcrystallinecellulose, and, optionally from about 0.25% to about 1.0%hydroxypropylmethylcellulose. The spheroids may be coated as describedabove, preferably with a film coating of from about 5% to about 10% byweight. In some preferred formulations, the spheroids comprise the citedvenlafaxine HCl and microcrystalline cellulose, with nohydroxypropylmethyl cellulose.

EXAMPLE NO. 6

[0050] Spheroids comprising 16.5% venlafaxine HCl and 83.5%microcrystalline cellulose were mixed with approximately 50% water (w/w)to granulate in a Littleford Blender Model FM-50E/1Z (Littleford DayInc., P.O. Box 128, Florence, Kent. 41022-0218, U.S.A.) at a fixed speedof 180 rpm. The blended material was extruded through a 1.25 mm screenusing a Nica extruder/spheronization machine (Aeromatic-FielderDivision, Niro Inc., 9165 Rumsey Rd., Columbia, Md. 21045, U.S.A.) for a12/20 mesh cut after drying. Two portions of the resulting spheroidswere coated with a 5% and 7% coating level, respectively, by techniquesdescribed above using the coating formulation: Ingredient % (w/w)Methylene Chloride 60.000 Methanol Anhydrous 35.500 Ethylcellulose, NF,HG 2834, 50 cps  3.825 Hydroxypropyl Methylcelluose, 2910 USP,  0.675 6cps

[0051] The 5% and 7% coated lots were tested for dissolution on aHewlett Packard automated dissolution system over a 24 hour period,resulting in the following dissolution patterns: % Dissoluded %Dissolved Time/hr 16.5%/5% 16.5%/7% 2 12.4  5.6 4 42.8 25.4 8 70.7 60.412  82.2 75.4 24  94.3 92.7

EXAMPLE NO. 7

[0052] A formulation of spheroids containing 8.25% venlafaxine HCl and91.75% microcrystalline cellulose was prepared according to thetechniques of Example No. 6 and coated with a 5% film coating. In theHewlett Packard automated dissolution system these spheroids providedthe following dissolution profile: % Dissolved Time/hr 8.25%/5% 2  4.4 424.2 8 62.9 12  77.8 24  93.5

[0053] Thus, the desired dissolution rates of sustained release dosageforms of venlafaxine hydrochloride, impossible to achieve with hydrogeltablet technology, has been achieved with the film-coated spheroidcompositions of this invention.

What is claimed is:
 1. An encapsulated, extended release formulation ofvenlafaxine hydrochloride comprising a pharmaceutically acceptablecapsule containing a therapeutically effective amount of venlafaxinehydrochloride in spheroids comprised of venlafaxine hydrochloride,microcrystalline cellulose and, optionally, hydroxypropylmethylcellulosecoated with a mixture of ethyl cellulose andhydroxypropylmethylcellulose.
 2. An extended release formulationaccording to claim 1 wherein the spheroids are comprised of from about6% to about 40% venlafaxine hydrochloride by weight, about 50% to about94% microcrystalline cellulose, NF, by weight, and, optionally, fromabout 0.25% to about 1% by weight of hydroxypropylmethylcellulose, USP.3. An extended release formulation according to claim 1 wherein thespheroids are coated with from about 2% to about 12% of totalformulation weight of film coating comprised of from about 80% to about90% by weight of film coating of ethyl cellulose, NF, and from about 10%to about 20% by weight of film coating of hydroxypropylmethylcellulose,USP.
 4. An extended release formulation according to claim 1 wherein thespheroids are comprised of from about 30% to 40% venlafaxinehydrochloride by weight, about 50% to about 70% microcrystallinecellulose, NF, by weight, and, optionally, from about 0.25% to about 1%by weight of hydroxypropylmethylcellulose, USP.
 5. An extended releaseformulation according to claim 4 wherein the spheroids are coated withfrom about 2% to about 12% of total formulation weight of film coatingcomprised of from about 80% to about 90% by weight of film coating ofethyl cellulose, NF, and from about 10% to about 20% by weight of filmcoating of hydroxypropylmethylcellulose, USP.
 6. An extended releaseformulation according to claim 1 wherein the spheroids comprise fromabout 6% to about 30% venlafaxine hydrochloride by weight, about 70.1%to about 94% microcrystalline cellulose, NF, by weight and, optionally,from about 0.25% to about 1% by weight of hydroxypropylmethylcellulose.7. An extended release formulation according to claim 6 wherein thespheroids are coated with from about 2% to about 12% of total weight offilm coating comprised of from about 80% to about 90% by weight of filmcoating of ethyl cellulose, NF, and from about 10% to about 20% byweight of film coating of hydroxypropylmethylcellulose, USP.
 8. Anextended release formulation according to claim 6 wherein the spheroidscomprise from about 5% to about 25% venlafaxine hydrochloride and fromabout 95% to about 75% microcrystalline cellulose, with an optionalamount of from 0.25% to about 1% by weight ofhydroxypropylmethylcellulose.
 9. An extended release formulationaccording to claim 6 wherein the spheroids comprise from about 6% toabout 25% venlafaxine hydrochloride and from about 94% to about 75%microcrystalline cellulose, with an optional amount of from 0.25% toabout 1% by weight of hydroxypropylmethylcellulose.
 10. An extendedrelease formulation according to claim 6 wherein the spheroids comprisefrom about 6% to about 20% venlafaxine hydrochloride and from about 94%to about 80% microcrystalline cellulose, with an optional amount of from0.25% to about 1% by weight of hydroxypropylmethylcellulose.
 11. Anencapsulated, extended release formulation of venlafaxine hydrochlorideaccording to claim 1 having the following dissolution profile in USPApparatus 1 (basket) at 100 rpm in purified water at 37° C.: Time(hours) Average % Venlafaxine HCl released 2 <30 4 30-55 8 55-80 12 65-90 24  >80


12. An extended release formulation according to claim 2 wherein thespheroids are composed of about 37% by weight of venlafaxinehydrochloride, about 0.5% by weight of hydroxypropylmethylcellulose2208, and about 62% by weight of microcrystalline cellulose.
 13. Acomposition according to claim 2 wherein the film coating is comprisedof ethyl cellulose (4.81% of total weight) andhydroxypropylmethylcellulose (0.85% of total weight).
 14. A compositionaccording to claim 2 wherein the film coating comprises 6-8% by weightof total weight.
 15. A composition according to claim 2 wherein the filmcoating is comprised of ethyl cellulose (2.48% of total weight) andhydroxypropylmethylcellulose (0.437% of total weight).
 16. A compositionaccording to claim 2 wherein film coating composition is comprised ofethyl cellulose having a 44.0-51.0% content of ethoxy groups andhydroxypropylmethylcellulose having a methoxy content of 28.0-30.0% anda hydroxypropoxy group content of 7.0-12.0%.
 17. A film coatingcomposition according to claim 2 which is comprised of about 85% bytotal weight of film coating of ethyl cellulose having a 44.0-51.0%content of ethoxy groups, and about 15% by total weight of film coatingof hydroxypropylmethylcellulose having a methoxy content of 28.0-30.0%and a hydroxypropoxy group content of 7.0-12.0%.
 18. A film coatingcomposition according to claim 2 which is comprised of 85% by weight ofethyl cellulose type HG 2834 and 15% by weight ofhydroxypropylmethylcellulose type
 2910. 19. An extended releaseformulation of venlafaxine hydrochloride for once daily administrationwhich comprises spheroids containing 37.3% venlafaxine, 62.17%microcrystalline cellulose and 0.5% hydroxypropylmethylcellulose type2208, coated with a quantity of a mixture comprised of 85% ethylcellulose type HG 2834 and 15% hydroxypropylmethylcellulose type 2910sufficient to give coated spheroids having a dissolution profile whichgives the desired release rate over a 24 hour period.
 20. An extendedrelease formulation of venlafaxine hydrochloride according to claim 2which provides peak serum levels of up to 150 ng/ml and extendedtherapeutically effective plasma levels over a twenty four hour period.21. A method for providing a therapeutic blood plasma concentration ofvenlafaxine over a twenty four hour period with diminished incidences ofnausea and emesis which comprises administering orally to a patient inneed thereof, an encapsulated, extended release formulation thatprovides a peak blood plasma level of venlafaxine in from about four toabout eight hours, said formulation containing venlafaxine hydrochlorideas the active ingredient.
 22. A method for eliminating the troughs andpeaks of drug concentration in a patients blood plasma attending thetherapeutic metabolism of plural daily doses of venlafaxinehydrochloride which comprises administering orally to a patient in needthereof, an encapsulated, extended release formulation that provides apeak blood plasma level of venlafaxine in from about four to about eighthours, said formulation containing venlafaxine hydrochloride as theactive ingredient.